Two major causes of disease include infectious agents and malfunctions of normal biological functions of an animal. Examples of infectious agents include viruses, bacteria, parasites, yeast and other fungi. Examples of abnormal biological function include uncontrolled cell growth, abnormal immune responses and abnormal inflammatory responses. Traditional reagents used attempt to protect an animal from disease include reagents that destroy infectious agents or cells involved in deregulated biological functions. Such reagents, however, can result in unwanted side effects. For example, anti-viral drugs that disrupt the replication of viral DNA also often disrupt DNA replication in normal cells in the treated patient. Other treatments with chemotherapeutic reagents to destroy cancer cells typically leads to side effects, such as bleeding, vomiting, diarrhea, ulcers, hair loss and increased susceptibility to secondary cancers and infections.
An alternative method of disease treatment includes modulating the immune system of a patient to assist the patient's natural defense mechanisms. Traditional reagents and methods used to attempt to regulate an immune response in a patient also result in unwanted side effects and have limited effectiveness. For example, immunosuppressive reagents (e.g., cyclosporin A, azathioprine, and prednisone) used to treat patients with autoimmune disease also suppress the patient's entire immune response, thereby increasing the risk of infection. In addition, immunopharmacological reagents used to treat cancer (e.g., interleukins) are short-lived in the circulation of a patient and are ineffective except in large doses. Due to the medical importance of immune regulation and the inadequacies of existing immunopharmacological reagents, reagents and methods to regulate specific parts of the immune system have been the subject of study for many years.
Stimulation or suppression of the immune response in a patient can be an effective treatment for a wide variety of medical disorders. T lymphocytes (T cells) are one of a variety of distinct cell types involved in an immune response. The activity of T cells is regulated by antigen, presented to a T cell in the context of a major histocompatibility complex (MHC) molecule. The T cell receptor (TCR) then binds to the MHC:antigen complex. Once antigen is complexed to MHC, the MHC:antigen complex is bound by a specific TCR on a T cell, thereby altering the activity of that T cell.
The use of certain staphylococcal enterotoxin proteins that are capable of complexing with MHC molecules to influence T cell function has been suggested by various investigators, including, for example, White et al., Cell 56:27-35, 1989; Rellahan et al. J. Expt. Med. 172:1091-1100, 1990; Micusan et al., Immunology 5:3-11, 1993; Hermann et al., Immunology 5:33-39, 1993; Bhardwaj et al., J. Expt. Med. 178:633-642, 1993; and Kalland et al., Med. Oncol. & Tumor Pharmacother., 10:37-47, 1993. In particular, various investigators have suggested that Staphylococcal enterotoxin proteins are useful for treating tumors, including Newell et al., Proc. Natl. Acad. Sci. USA 88:1074-1078, 1991; Kalland et al., PCT Application No. WO 91/04053, published Apr. 4, 1991; Dohlstein et al., Proc. Natl. Acad. Sci. USA 88:9287-9291, 1991; Hedlund et al., Cancer Immunol. Immunother. 36:89-93, 1993; Lando et al., Cancer Immunol. Immunother. 36:223-228, 1993; Lukacs et al., J. Exp. Med. 178:343-348, 1993; Ochi et al., J. Immunol. 151:3180-3186, 1993; and Terman et al., PCT Application No. WO 93/24136, published Dec. 9, 1993. These investigators, however, have only disclosed the use of bacterial enterotoxin proteins themselves. The use of bacterial enterotoxin protein has the major disadvantage of being toxic to the recipient of the protein.
Thus, there is a need for a product and process that allows for the treatment of disease using bacterial enterotoxins in a non-toxic manner.